Heat-resistant action potentials require TTX-resistant sodium channels NaV1.8 and NaV1.9.

Damage-sensing nociceptors in the skin provide an indispensable protective function thanks to their specialized ability to detect and transmit hot temperatures that would block or inflict irreversible damage in other mammalian neurons. Here we show that the exceptional capacity of skin C-fiber nociceptors to encode noxiously hot temperatures depends on two tetrodotoxin (TTX)-resistant sodium channel α-subunits: Na_V1.8 and Na_V1.9. We demonstrate that Na_V1.9, which is commonly considered an amplifier of subthreshold depolarizations at 20°C, undergoes a large gain of function when temperatures rise to the pain threshold. We also show that this gain of function renders Na_V1.9 capable of generating action potentials with a clear inflection point and positive overshoot. In the skin, heat-resistant nociceptors appear as two distinct types with unique and possibly specialized features: one is blocked by TTX and relies on Na_V1.9, and the second type is insensitive to TTX and composed of both Na_V1.8 and Na_V1.9. Independent of rapidly gated TTX-sensitive Na_V channels that form the action potential at pain threshold, Na_V1.8 is required in all heat-resistant nociceptors to encode temperatures higher than ∼46°C, whereas Na_V1.9 is crucial for shaping the action potential upstroke and keeping the Na_V1.8 voltage threshold within reach.